Philippe Marambaud, PhD, an assistant investigator at The Feinstein Institute for Medical Research, and Fabien Campagne, PhD, of The Weill Medical College of Cornell University, began focusing their search for genes expressed in the hippocampus, an area that is hit early in the disease process. They identified several polymorphisms – or gene variants – in DNA samples from Alzheimer’s patients and controls, and one stood out preferentially in the Alzheimer’s brains in a previously uncharacterized gene. The authors found a new calcium channel modulator strongly expressed in the hippocampus, a brain region necessary for learning and memory.
Normally, channels work like a bridge to open up and allow boats to pass. In this case, the channel opens and allows calcium into the neuron, a mechanism that controls important signals inside the cells, such as memory formation. The study was published in the journal Cell. The risk gene, called CALHM1, leads to a partial loss of function, which means that less calcium gets into the cell and it weakens the signals normally regulated by calcium. The authors determined that one of these signals controls the levels of amyloid peptides, the building blocks of the characteristic senile plaques.
The researchers conducted the study using DNA from American deceased Alzheimer’s and age-matched controls with no pathological signs of the disease. They also collaborated with French researcher Jean Charles Lambert, PhD, who had access to DNA samples from patients in France, Italy and the United Kingdom. In total, they ran tests on 3,404 samples. The gene variant showed up more often in the Alzheimer’s samples. People who have the genetic variant have 1.5 times higher risk of developing Alzheimer’s.
The strongest risk gene identified for late-onset Alzheimer’s is Apo-E4. Just one copy of this gene variant triples the risk of the disease. No one knows precisely why or how it works to increase the risk for the disease. Dr. Marambaud and his colleagues are excited by their discovery, because there are medicines that block calcium channels and it would be easier to develop targeted therapies.
“It is a lot easier to figure out how to alter this effect of this gene compared to Apo-E4,” said Peter Davies, PhD, head of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease and Memory Disorders. "This is the kind of target that pharmaceutical companies are familiar with. Calcium channel drugs have been well studied for decades.”
He added that a lot more basic science work is needed before such drugs are developed. They want to figure out what this newly identified modulator of calcium channel does in the normal brain, and then how it precisely works to increase the risk for Alzheimer’s.
"This is a robust genetic risk factor that was identified now in four different populations,” said Dr. Marambaud. “Having this risk gene can cause a functional problem. It may not only affect the balance of calcium in the brain, which is key to normal cellular processing in memory formation, but also increases the formation of the amyloid peptide, a key player in the pathogenic process of the disease”. He said that the gene, located on chromosome 10, is restricted primarily to the brain. This new work not only provides a better understanding of the pathogenic mechanisms leading to the disease but also identifies CALHM1 as a potentially important new target for therapy.
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